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Mood disorders including major depressive disorder (MDD) are one of the most important causes of disability for human health and the second leading source of disease burden, going beyond cardiovascular diseases, dementia, lung cancer, and diabetes. The comorbidity of depression and substance use disorder (SUD) has been well-established. While there are over 6,000 studies on genes and depression, a definitive human gene map of depression still eludes the field of psychiatric genetics. Certainly, GWAS and candidate approaches are on-going and hold out promise for the future. It is our contention that one approach involves the induction of true "dopamine homeostasis" easier said than done. In this treatise, we are suggesting a novel therapeutic modality that includes DNA genotyping based on a Genetic Addiction Risk Score (GARS) test and concomitant alteration of a Pro-dopamine Regulator (KB220) contents linked to personalized polymorphisms observed in the genes across the brain reward circuitry in the prefrontal cortex and mesolimbic systems.